Chong Elise A, Penuel Elicia, Napier Ellen B, Lundberg Rachel K, Budde Lihua E, Shadman Mazyar, Matasar Matthew J, Bartlett Nancy L, Flinn Ian W, Bosch Francesc, Fay Keith, Goy Andre, Kumar Anita, Nastoupil Loretta J, Wei Michael C, Wu Mei, Yin Shen, Fraietta Joseph A, Chong Emeline R, Schuster Stephen J
Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA.
Genentech, Inc, South San Francisco, CA.
Blood Adv. 2025 Feb 25;9(4):696-703. doi: 10.1182/bloodadvances.2024013640.
Mosunetuzumab and other CD20/CD3 bispecific antibodies (BsAbs) have efficacy in B-cell lymphomas relapsing after or refractory to CD19-directed chimeric antigen receptor (CAR)-modified T cells (CAR-T). The optimal timing of BsAbs and biomarkers of BsAb response after CAR-T are unknown. We addressed these questions using clinical data and blood samples from patients previously treated with CAR-T and subsequently treated on a phase 1/2 study of mosunetuzumab. Thirty patients had paired samples at baseline and after 1 cycle of mosunetuzumab. The median time from CAR-T to mosunetuzumab was significantly longer for responding than for nonresponding patients (P = .006, unadjusted for multiple comparisons). Most patients (20/30) did not receive intervening therapy between CAR-T administration and mosunetuzumab. The remainder of patients received 1 intervening therapy after a protocol-mandated drug washout. After mosunetuzumab, responding patients had higher lymphocytes (995 vs 400 cells per μL; P = .02) and greater increases in CD4 and CD8 cells (median change, 73 vs -90 cells per μL [P = .005] and 243 vs -103 cells per μL [P = .004], respectively). Additionally, responding patients had an increase in activated CD8 cells (median fold change, 1.7; P = .02). Nonresponders had a relative decrease in CAR transgene levels (n = 16; P = .04). This is, to our knowledge, the first study to assess changes in lymphocytes, T cells, and CAR transgene levels in patients treated with BsAbs after CAR-T. These findings suggest an interaction between prior CAR-T and BsAb outcomes and have implications for optimal timing of BsAb after CAR-T. The trial was registered at www.ClinicalTrials.gov as #NCT02500407.
莫苏奈妥珠单抗和其他CD20/CD3双特异性抗体（BsAbs）对在接受靶向CD19的嵌合抗原受体（CAR）修饰的T细胞（CAR-T）治疗后复发或难治的B细胞淋巴瘤有效。BsAbs的最佳使用时机以及CAR-T治疗后BsAb反应的生物标志物尚不清楚。我们利用曾接受CAR-T治疗且随后参加莫苏奈妥珠单抗1/2期研究的患者的临床数据和血样来解决这些问题。30例患者在基线期和接受1个周期莫苏奈妥珠单抗治疗后有配对样本。从CAR-T治疗到使用莫苏奈妥珠单抗的中位时间，有反应的患者显著长于无反应的患者（P = 0.006，未针对多重比较进行校正）。大多数患者（20/30）在CAR-T治疗与使用莫苏奈妥珠单抗之间未接受中间治疗。其余患者在方案规定的药物洗脱期后接受了1次中间治疗。使用莫苏奈妥珠单抗后，有反应的患者淋巴细胞水平较高（每微升995个细胞对400个细胞；P = 0.02），CD4和CD8细胞增加幅度更大（中位变化分别为每微升73个细胞对 -90个细胞[P = 0.005]和每微升243个细胞对 -103个细胞[P = 0.004]）。此外，有反应的患者活化CD8细胞增加（中位倍数变化，1.7；P = 0.02）。无反应者的CAR转基因水平相对降低（n = 16；P = 0.04）。据我们所知，这是第一项评估CAR-T治疗后接受BsAbs治疗患者淋巴细胞、T细胞和CAR转基因水平变化的研究。这些发现提示既往CAR-T与BsAb疗效之间存在相互作用，并对CAR-T治疗后BsAb的最佳使用时机具有启示意义。该试验在www.ClinicalTrials.gov上注册，编号为#NCT02500407。
